During carcinogenesis, malignant cells with abnormally high proteolytic activity degrade extracellular matrix proteins facilitating invasion and metastasis. In cancer-related angiogenesis, proteolytic activity is high at the tip of the capillary vessels, which allows the formation of a dense network of neovasculature in the proximity of the tumor mass to support cancer growth (Lah et al., 2006, Expert Opin Biol Ther 6:257-279; Ludwig, 2005, Bioessays 27:1181-1191). Consequently, inhibition of proteolysis has been explored as a therapeutic option to limit invasion, metastasis and angiogenesis (Schirrmacher, 1985, Adv Cancer Res 43:1-73; Swiercz et al., 2001, Oncol Rep 8:463-470; Vihinen et al., 2005, Curr Cancer Drug Targets 5:203-220).
Attention has been concentrated on the inhibition of metalloproteinases. Certain metalloproteinase inhibitors are in the clinical studies (Arlen et al., 2006, Clin Cancer Res 12:1260-1269; Lara et al., 2006, Clin Cancer Res 12:1556-1563; Molina et al., 2005, Anticancer Drugs 16:997-1002).
Much less consideration has been paid to inhibition of enzymes leading to formation of plasmin, an enzyme that can either directly or indirectly hydrolyze many extracellular domain proteins. Plasmin is produced from plasminogen by the plasminogen activators, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA). Certain plasmin inhibitors have also shown strong anticancer activity in preclinical studies (Chorostowska-Wynimko et al., 2003, Mol Cancer Ther 2:19-28; Jedinak et al., 2005, Neoplasma 52:185-192; Puli et al., 2006, J Neurooncol).
For example, inhibitors of uPA prevent plasmin formation and consequently limit cancer growth by blocking angiogenesis (Swiercz et al., 2001, Oncol Rep 8:463-470; Inoue et al., 2005, Oncol. Rep. 14:1445-1451; van Hinsbergh et al., 2006, Arterioscler Thromb Vasc Biol 26:716-728). Inhibitors or uPA, however, are generally considered toxic or labile.
In addition, modified PAI-1 molecules have been identified that exhibit an increased half-life of the active form (US2005/0158295A1). PAI-1 is a member of the super-class of Serine Protease Inhibitors (serpin) that inhibits uPA and tPA activity, increasing the half-life of the active (versus latent) form of PAI-1 is useful in cancer therapy.
Given the importance of proteases and proteolytic cascades in the cancer process, a need continues to exist for the identification and development of appropriate modulators thereof.